Steroid receptors regulate the expression of myriad target genes involved in metabolism,[unreadable] development, and reproduction. Nuclear receptors (NRs) are activated, usually by ligands, and[unreadable] relocate to specific DMA binding sites at target gene promoters where they accumulate an array of[unreadable] coactivators (or corepressors) that carry out the series of transcriptional substeps required for[unreadable] modulating gene expression. The SRC/p160 family of coactivators appears to play a fundamental[unreadable] role in this latter regard. We hypothesize that NRs and their attendant coactivators have evolved as[unreadable] the primary regulators of adipocyte development and of metabolic pathways in fat cells and other[unreadable] metabolic tissues. Toward the goal of elucidating these pathways that control lipid and[unreadable] carbohydrate metabolism, we plan to carry out investigations of the genetic, structural, regulatory[unreadable] and metabolic fingerprints of COUP-TFs and SRC family coactivators in cell extracts, in cells and in[unreadable] animals. We intend to: (1) elucidate the mechanisms by which COUP-TFII regulates adipocyte[unreadable] differentiation; (2) define the role by which SRC-3 controls the onset of the chain of transcriptional[unreadable] events leading to adipocyte developmental function; (3) define the roles of SRC coactivators in[unreadable] coordinately activating (or repressing) their target genes to effect spatiotemporal regulation of[unreadable] metabolic pathways in liver, muscle and fat cells; and (4) define the functional phenotypic effects of[unreadable] the SRC coactivators in controlling lipid and carbohydrate functions in the whole animal and[unreadable] examine the mechanism by which animal genotype modifies such coactivator phenotypic functional[unreadable] diversity. We will employ an integrative methodological approach to prove our hypothesis which[unreadable] uses cellular biology, biochemistry, physical chemistry, microscopy, nucleic acid and transgenic[unreadable] biology, bioinformatics, genetics and animal physiology in 4 Projects and 2 Core Labs. This[unreadable] information will lead to a much greater understanding of nuclear receptor and coactivator biology[unreadable] that would uncover new intervention points to aid in the design of novel therapies for metabolic[unreadable] disorders.